MYC promotes cancer progression by modulating m6A modifications to suppress target gene translation

被引：33

作者：

Wu, Gongwei ^{[1
,2
]}

Suo, Caixia ^{[1
,3
]}

Yang, Ying ^{[4
]}

Shen, Shengqi ^{[2
]}

Sun, Linchong ^{[1
,3
]}

Li, Shi-Ting ^{[2
]}

Zhou, Yingli ^{[2
]}

Yang, Dongdong ^{[2
]}

Wang, Yan ^{[2
]}

Cai, Yongping ^{[5
]}

Wang, Nana ^{[5
]}

Zhang, Huafeng ^{[2
]}

Yang, Yun-Gui ^{[4
,6
,7
,8
]}

Cao, Jie ^{[1
,3
]}

Gao, Ping ^{[1
,2
,9
]}

机构：

[1] South China Univ Technol, Inst Life Sci, Sch Med, Guangzhou Peoples Hosp 1, Guangzhou, Peoples R China

[2] Univ Sci & Technol China, CAS Key Lab Innate Immun & Chron Dis, Innovat Ctr Cell Signaling Network, Sch Life Sci, Hefei, Anhui, Peoples R China

[3] South China Univ Technol, Sch Biomed Sci & Engn, Guangzhou Int Campus, Guangzhou, Peoples R China

[4] Chinese Acad Sci, Collaborat Innovat Ctr Genet & Dev, CAS Ctr Excellence Mol Cell Sci, Key Lab Genom & Precis Med,Beijing Inst Genom, Beijing, Peoples R China

[5] Anhui Med Univ, Sch Med, Dept Pathol, Hefei, Anhui, Peoples R China

[6] Univ Chinese Acad Sci, Beijing, Peoples R China

[7] China Natl Ctr Bioinformat, Beijing, Peoples R China

[8] Chinese Acad Sci, Inst Stem Cell & Regenerat, Beijing, Peoples R China

[9] Guangzhou Regenerat Med & Hlth Guangdong Lab, Guangzhou, Peoples R China

来源：

EMBO REPORTS | 2021年 / 22卷 / 03期

基金：

中国国家自然科学基金; 国家重点研发计划;

关键词：

ALKBH5; m(6)A; MYC; MYC-repressed genes; oncogenesis; C-MYC; RNA; EXPRESSION; TRANSCRIPTION; DEMETHYLASE; ACTIVATION; REPRESSION; METHYLTRANSFERASE; REARRANGEMENT; METHYLATION;

D O I：

10.15252/embr.202051519

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The MYC oncoprotein activates and represses gene expression in a transcription-dependent or transcription-independent manner. Modification of mRNA emerges as a key gene expression regulatory nexus. We sought to determine whether MYC alters mRNA modifications and report here that MYC promotes cancer progression by down-regulating N6-methyladenosine (m(6)A) preferentially in transcripts of a subset of MYC-repressed genes (MRGs). We find that MYC activates the expression of ALKBH5 and reduces m(6)A levels in the mRNA of the selected MRGs SPI1 and PHF12. We also show that MYC-regulated m(6)A controls the translation of MRG mRNA via the specific m(6)A reader YTHDF3. Finally, we find that inhibition of ALKBH5, or overexpression of SPI1 or PHF12, effectively suppresses the growth of MYC-deregulated B-cell lymphomas, both in vitro and in vivo. Our findings uncover a novel mechanism by which MYC suppresses gene expression by altering m(6)A modifications in selected MRG transcripts promotes cancer progression.

引用

页数：15

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